WO2021214502A1 - Process for preparing a phthalazinone derivative and intermediates thereof - Google Patents
Process for preparing a phthalazinone derivative and intermediates thereof Download PDFInfo
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- WO2021214502A1 WO2021214502A1 PCT/IB2020/000318 IB2020000318W WO2021214502A1 WO 2021214502 A1 WO2021214502 A1 WO 2021214502A1 IB 2020000318 W IB2020000318 W IB 2020000318W WO 2021214502 A1 WO2021214502 A1 WO 2021214502A1
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- Prior art keywords
- formula
- compound
- acid
- protecting group
- methyl
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- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 239000000543 intermediate Substances 0.000 title abstract description 29
- IJAPPYDYQCXOEF-UHFFFAOYSA-N phthalazin-1(2H)-one Chemical class C1=CC=C2C(=O)NN=CC2=C1 IJAPPYDYQCXOEF-UHFFFAOYSA-N 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 164
- 238000000034 method Methods 0.000 claims abstract description 74
- 239000000203 mixture Substances 0.000 claims abstract description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 90
- 239000002253 acid Substances 0.000 claims description 63
- 150000003839 salts Chemical class 0.000 claims description 61
- 125000006242 amine protecting group Chemical group 0.000 claims description 47
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 29
- -1 p-methoxybenzyl Chemical group 0.000 claims description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- 239000002585 base Substances 0.000 claims description 24
- UOWHCAKKYIRMSX-UHFFFAOYSA-N [N].C1CNC1 Chemical group [N].C1CNC1 UOWHCAKKYIRMSX-UHFFFAOYSA-N 0.000 claims description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 13
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 10
- 229940071870 hydroiodic acid Drugs 0.000 claims description 10
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 9
- 229940088679 drug related substance Drugs 0.000 claims description 9
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 8
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 230000000269 nucleophilic effect Effects 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- KZRKEGBOXZQAGC-UHFFFAOYSA-N OC(N(CC1CNC1)C1(CC2C(C=CC=C3)=C3C3=CC=CC=C23)CC1)=O.Cl Chemical compound OC(N(CC1CNC1)C1(CC2C(C=CC=C3)=C3C3=CC=CC=C23)CC1)=O.Cl KZRKEGBOXZQAGC-UHFFFAOYSA-N 0.000 claims description 4
- SIIJRCRHAIMFNT-UHFFFAOYSA-N cyclopropanamine;hydrochloride Chemical compound Cl.NC1CC1 SIIJRCRHAIMFNT-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- ZMKYAECYGFEYTQ-UHFFFAOYSA-N 4-[[3-[3-[[cyclopropyl-[(4-methoxyphenyl)methyl]amino]methyl]azetidine-1-carbonyl]-4-fluorophenyl]methyl]-2H-phthalazin-1-one Chemical compound C1(CC1)N(CC1=CC=C(C=C1)OC)CC1CN(C1)C(=O)C=1C=C(CC2=NNC(C3=CC=CC=C23)=O)C=CC=1F ZMKYAECYGFEYTQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012661 PARP inhibitor Substances 0.000 claims description 3
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 claims description 3
- KVVMXWRFYAGASO-UHFFFAOYSA-N azetidine-1-carboxylic acid Chemical compound OC(=O)N1CCC1 KVVMXWRFYAGASO-UHFFFAOYSA-N 0.000 claims description 3
- CLIHFNNXSRJMEJ-UHFFFAOYSA-N C1=CC=CC=2C3=CC=CC=C3C(C1=2)COC(=O)N(C1CC1)CC1CN(C1)C(=O)OC(C)(C)C Chemical compound C1=CC=CC=2C3=CC=CC=C3C(C1=2)COC(=O)N(C1CC1)CC1CN(C1)C(=O)OC(C)(C)C CLIHFNNXSRJMEJ-UHFFFAOYSA-N 0.000 claims description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims 3
- OPFZKTDFSWTZSS-UHFFFAOYSA-N CC(C)(C)C1=C(CN(CC(C=C2)=CC=C2OC)C2CC2)[C-]=[NH+]1 Chemical compound CC(C)(C)C1=C(CN(CC(C=C2)=CC=C2OC)C2CC2)[C-]=[NH+]1 OPFZKTDFSWTZSS-UHFFFAOYSA-N 0.000 claims 1
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 27
- YNBQAYKYNYRCCA-UHFFFAOYSA-N venadaparib Chemical compound C1(CC1)NCC1CN(C1)C(=O)C=1C=C(CC2=NNC(C3=CC=CC=C23)=O)C=CC1F YNBQAYKYNYRCCA-UHFFFAOYSA-N 0.000 abstract description 12
- 239000000047 product Substances 0.000 abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
- 238000006243 chemical reaction Methods 0.000 description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000007864 aqueous solution Substances 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 238000000746 purification Methods 0.000 description 11
- 239000007790 solid phase Substances 0.000 description 11
- 238000010992 reflux Methods 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 229940093499 ethyl acetate Drugs 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 150000002576 ketones Chemical class 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 4
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 4
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- KASYKNWLVMRDCN-UHFFFAOYSA-N tert-butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CC1CNC1CC1 KASYKNWLVMRDCN-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 3
- PAXLJNGPFJEKQX-UHFFFAOYSA-N 2-fluoro-5-[(4-oxo-3h-phthalazin-1-yl)methyl]benzoic acid Chemical compound C1=C(F)C(C(=O)O)=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=C1 PAXLJNGPFJEKQX-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 150000002168 ethanoic acid esters Chemical class 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- 239000011369 resultant mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 2
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 2
- MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 description 2
- LQVMZVKOVPITOO-UHFFFAOYSA-N 9h-fluoren-1-ylmethyl carbonochloridate Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)Cl)=CC=C2 LQVMZVKOVPITOO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BCIVDTFIBZOAQA-UHFFFAOYSA-N C1=CC=CC=2C3=CC=CC=C3C(C1=2)COC(N(CC1CN(C1)C(C1=C(C=CC(=C1)CC1=NNC(C2=CC=CC=C12)=O)F)=O)C1CC1)=O Chemical compound C1=CC=CC=2C3=CC=CC=C3C(C1=2)COC(N(CC1CN(C1)C(C1=C(C=CC(=C1)CC1=NNC(C2=CC=CC=C12)=O)F)=O)C1CC1)=O BCIVDTFIBZOAQA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 125000002393 azetidinyl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 125000006317 cyclopropyl amino group Chemical group 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- PHVXTQIROLEEDB-UHFFFAOYSA-N n-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-n-pyrrolidin-3-ylbenzamide Chemical compound CC1=CC=CC=C1C1CN(CC=2C=CC(=CC=2)C(=O)N(CCC=2C(=CC=CC=2)Cl)C2CNCC2)CCC1 PHVXTQIROLEEDB-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- JWEQRJSCTFBRSI-PCLIKHOPSA-N rboxylate Chemical compound COC(=O)C1C(N2C3=O)C4=CC=CC=C4OC1(C)N=C2S\C3=C\C(C=1)=CC=C(OC)C=1COC1=CC=CC=C1C JWEQRJSCTFBRSI-PCLIKHOPSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 150000003335 secondary amines Chemical group 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- ASQOQJYHIYYTEJ-GBESFXJTSA-N (1r,7s,9as)-7-decyl-2,3,4,6,7,8,9,9a-octahydro-1h-quinolizin-1-ol Chemical compound O[C@@H]1CCCN2C[C@@H](CCCCCCCCCC)CC[C@H]21 ASQOQJYHIYYTEJ-GBESFXJTSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
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- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 1
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to methods of preparing phthalazinone derivatives which are poly (ADP-ribose) polymerase (PARP) inhibitors, intermediates used in these preparation methods, methods of preparing the intermediates, and compositions and products comprising said derivatives prepared from methods that result in high purity and yield.
- PARP poly (ADP-ribose) polymerase
- Patent document 1 discloses phthalazinone derivatives having anti-cancer activity as poly( ADP-ribose) polymerase (PARP) inhibitors, racemates, enantiomers or diastereomers thereof, or pharmaceutically acceptable salts thereof.
- PARP ADP-ribose polymerase
- Example 143 Step 2
- the reaction is not completed even when the reaction proceeds for 24 hours or longer. Further, due to the generation of a plurality of related materials, an additional purification step, including column chromatography, is necessary to obtain substantially pure sample, which diminishes the final yield.
- Patent Document Patent document 0001
- Patent document 0001 US 9,682,973
- An aspect of the present invention is to provide a method of preparing 4-[3-(3- [(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one, or a pharmaceutically acceptable salt thereof, where one or more intermediates are obtained in a solid phase, and where the reduction in the formation of impurities avoids the need for an additional purification step, thereby increasing the total yield in a manner that is suitable for mass (e.g., large-scale and commercial) production.
- Another aspect is to provide one or more novel intermediates which can be used in the above-described preparation method.
- Another aspect is to provide a method of preparing the one or more intermediates.
- compositions and products containing the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, prepared from the methods of the present invention are also provided.
- a method of preparing a compound of Formula 1 or a pharmaceutically acceptable salt thereof: [Formula 1j the method comprising a step (a2) of deprotecting a compound of Formula 4 to prepare the compound of Formula 1 :
- a method of preparing a compound of Formula 4 comprising a step (a1) of reacting a compound of Formula 2 with a compound of Formula 3:
- X 2 is an azetidine nitrogen protecting group, and HA is an acid which forms an acid addition salt. According to another aspect of the present invention, there is provided a compound of Formula 2:
- HA is an acid which forms an acid addition salt.
- one or more intermediates generated according to the present method may be obtained in a solid phase, thus resulting in more convenient separation of the intermediates.
- the reaction to generate intermediates may be completed with minimal side reactions, and low levels of impurities, and thus there is no need to perform column chromatography, which was previously needed for separation and purification to obtain substantially pure compound. Due to the reduction in the generation of impurities and easy separation of the intermediates, a final product may be obtained with high purity and high yield.
- the preparation method according to an aspect of the present invention may prepare 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4- fluorobenzyl]phthalazin-1 (2H)-one, or a pharmaceutically acceptable salt thereof, with higher purity and higher yield, and more economically, and thus is suitable for mass ( e.g ., large-scale and commercial) production.
- protecting group refers to a functional group which protects, from unintentional reaction, a functional group such as an amino group or alcohol group, by being bonded thereto via a covalent bond, and allows the functional group to be regenerated (i.e., de-protected) after treatment of the protecting group with a suitable reagent.
- the term "intermediates generated according to the present method are obtained in a solid phase" means that the intermediates are obtained in a solid form by, for example, filtration and drying, or similar steps known in the art.
- ambient temperature refers to an indoor ambient temperature in the range of about 1 °C to about 30 °C.
- An aspect of the present invention provides a method of preparing a compound of Formula 1 , or a pharmaceutically acceptable salt thereof,
- X 1 is an amine protecting group
- the compound of Formula 4 may be prepared by a step (a1 ) of reacting a compound of Formula 2 with a compound of Formula 3:
- Another aspect of the present invention provides a method of preparing a compound of Formula 4, including a step (a1) of reacting a compound of Formula 2 with a compound of Formula 3:
- X 1 is an amine protecting group
- HA is an acid which forms an acid addition salt
- HA may be any acid which forms an acid addition salt.
- the acid addition salt may be a hydrohalogenic acid salt.
- the hydroha logenic acid may include hydrochloric acid (HCI), hydrobromic acid (HBr), or hydroiodic acid (HI), and preferably, hydrochloric acid (HCI).
- the compound of Formula 4 may be obtained by amide bond between the compound of Formula 2 and the compound of Formula 3.
- the compound of Formula 1 may be obtained by removing X 1 which is a protecting group for the amine group of the compound of Formula 4.
- the method of preparing the compound of Formula 1 may be represented by Reaction Scheme 2 below.
- the compound of Formula 3 used in the step (a1) may be prepared according to any method known in the art, for example, a method disclosed in WO 2004/080976 (see section b in "Synthesis of Key Intermediates”).
- the compound of Formula 2 may be in the form of hydrochloride salt wherein HA is hydrochloric acid.
- X 1 may be any amine protecting group capable of protecting the amine group to which X 1 is bonded in the reaction of step (a1 ). This amine protecting group may include, but is not limited to, fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), or p-methoxy benzyl (PMB).
- the step (a1) of preparing the compound of Formula 4 may be carried out under any condition which allows formation of amide bond between the azetidine amine of the compound of Formula 2 and the carboxyl group of the compound of Formula 3.
- the step (a1 ) may be carried out in the presence of an amide coupling reagent.
- the amide coupling reagent refers to a reagent which activates a carboxyl group of a reactant to be able to form an amide group during reaction with an amine.
- the amide coupling reagent may include, but not limited to, trimethylacetyl chloride, 1 ,T-carbonyldi imidazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDC), or any combination thereof.
- the step (a1) may be carried out in the presence of a base, for example, in the presence of at least one base selected from the group consisting of diisopropylethylamine, triethylamine, N-methy I morpholine, and any combination thereof.
- the step (a1 ) may be carried out in the presence of both at least one amide coupling reagent and at least one base.
- the step (a1 ) may be carried out in the presence of both at least one amide coupling agent selected from the group consisting of trimethylacetyl chloride, 1 ,T-carbonyldi imidazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDC), and any combination thereof, and at least one base selected from the group consisting of diisopropylethylamine, triethylamine, N-methylmorpholine, and any combination thereof.
- at least one amide coupling agent selected from the group consisting of trimethylacetyl chloride, 1 ,T-carbonyldi imidazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDC), and any combination thereof
- EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochlor
- a solvent which does not inhibit the reaction may be used.
- the solvent may be selected from acetonitrile, acetone, toluene, tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide, and any combination thereof.
- the solvent may be toluene.
- the reaction in the step (a1 ) may be carried out at a temperature of about -20 °C to a reflux temperature, and in some embodiments, at about -20 °C to about 120 °C, and in other embodiments, about -10 °C to about 40 °C.
- the compound of Formula 4 which is the product of the reaction, may be obtained in solid phase.
- the compound of Formula 4 may be obtained in solid form by filtration and drying.
- the step (a2) of preparing the compound of Formula 1 is a reaction of removing the amine protecting group X 1 from the compound of Formula 4, and the reaction conditions for removing the amine protecting group X 1 may vary depending on the type of the amine protecting group X 1 .
- the step (a2) of preparing the compound of Formula 1 may include, when X 1 is fluorenylmethoxycarbonyl (Fmoc), reacting the compound of Formula 4 with a non-nucleophilic base.
- the non-nucleophilic base is not limited to specific types, and may be any non-nucleophilic base which can effectively remove the amine protecting group X 1 .
- the non-nucleophilic base may be selected from piperidine, diisopropylethylamine, 1 ,8-diazabicyclo[5,4,0]undec-7-ene, and any combination thereof.
- a solvent for the reaction in the step (a2) may be acetonitrile, tetrahydrofuran, N,N-dimethylformamide, or any combination thereof.
- X 1 is fluorenylmethoxycarbonyl (Fmoc)
- the non-nucleophilic base and the solvent may be, respectively, piperidine and acetonitrile, diisopropylethylamine and tetrahydrofuran, or 8- diazabicyclo[5,4,0]undec-7-ene and N,N-dimethylfomnamide.
- the compound of Formula 4 may be reacted with an alkali base.
- the alkali base is not limited to specific types, and may be any alkali base which can effectively separate the amine protecting group X 1 .
- the alkali base may be potassium hydroxide, potassium carbonate, sodium hydroxide, sodium carbonate, or any combination thereof.
- a solvent for the reaction in the step (a2) may be a solvent in which water is added to a C 1 -C 4 linear alcohol, a C 1 -C 4 branched alcohol, or any combination thereof.
- the alkali base and the solvent may be, respectively, potassium hydroxide and isopropyl alcohol/water, potassium carbonate and methanol/water, sodium hydroxide and methanol/ water, or sodium carbonate and ethanol/water.
- the compound of Formula 4 in the step (a2), when X 1 is p-methoxy benzyl (PMB), the compound of Formula 4 may be reacted with an acid.
- the acid is not limited to specific types, and may be any acid which can effectively remove the amine protecting group.
- trif!uoroacetic acid may be used as the reagent and a solvent.
- a ratio (w/v) of the weight of the compound of Formula 4 and the volume of trifluoroacetic acid may be about 1 :5 to about 1 :40.
- a ratio (w/v) of the compound of Formula 4 to trifluoroacetic acid which are used in the reaction of the step (a2), may be about 1:10.
- the compound of Formula 1 which is the product of the reaction, may be obtained in solid phase.
- the compound of Formula 1 may be obtained in solid form by filtration and drying.
- a step (a3) of preparing an acid addition salt of the compound of Formula 1 by reacting the compound of Formula 1 with an acid may be further performed to thereby prepare a pharmaceutically acceptable salt of the compound of Formula 1.
- the preparing of an acid addition salt of the compound of Formula 1 may be performed using a suitable method by those skilled in the art based on the common knowledge in the field of organic chemistry.
- the acid addition salt of the compound of Formula 1 may be any pharmaceutically acceptable acid addition salt, for example, an acid addition salt formed from a free acid.
- the free acid may be an inorganic acid or an organic acid.
- the inorganic acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid.
- the organic acid may be, but not limited to, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, adipic acid, L- or D-tartaric acid, DL-tartaric acid, citric acid, lactic acid, benzoic acid, mandelic acid, salicylic acid, cinnamic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid, glycolic acid, pyruvic acid, glucuronic acid, glutamic acid, aspartic acid, or any combination thereof.
- the acid addition salt may be an inorganic acid addition salt, and in an embodiment, a hydrochloric acid addition salt.
- the reaction in the step (a) of preparing an acid addition salt of the compound of Formula 1 may be carried out in any solvent which does not inhibit formation of the acid addition salt.
- the solvent may be selected from alcohol, ketone, ether, acetic acid esters, dichloromethane, chloroform, and any combination thereof, and in some embodiments, may be a C 1 -C 5 alcohol, a C 3 -C 10 ketone, a C 2 -C 10 ether, C 2 -C 4 alkyl acetate, dichloromethane, chloroform, or any combination thereof.
- the reaction in the step (a3) may be carried out at a temperature of about -20 °C to a reflux temperature, and in some embodiments, at a temperature ranging from about -20°C to about 50 °C, and in other embodiments, at a temperature ranging from about - 10°C to about 30 °C.
- a hydrochloride of the compound of Formula 1 may be prepared by adding, at a temperature ranging from about -20 °C to a reflux temperature, anhydrous hydrochloric acid or concentrated hydrochloric acid to the compound represented by Formula 1 , with a solvent of an alcohol, a mixture of alcohol and ketone, a mixture of alcohol and dichloromethane, a mixture of alcohol and chloroform, a mixture of alcohol and ether, or a mixture of alcohol and acetic acid esters.
- the alcohol, the ketone, the ether, and the acetic acid esters may be, respectively, a C 1 -C 5 alcohol, a C 3 -C 10 ketone, a C 2 -C 10 ether, and C 2 -C 4 alkyl acetate.
- a hydrochloride of the compound of Formula 1 may be prepared by adding, at a temperature ranging from about -20 °C to a reflux temperature or less, anhydrous hydrochloric acid or concentrated hydrochloric acid to the compound represented by Formula 1 , with a solvent of an alcohol, a mixture of alcohol and ketone, a mixture of alcohol and dichloromethane, a mixture of alcohol and chloroform, or a mixture of alcohol and ether, and then filtering and drying the thus-formed solid.
- the alcohol, the ketone, and the ether may be, respectively, a C 1 -C 5 alcohol, a C 3 -C 10 ketone, and a C 2 -C 10 ether.
- the acid addition salt of the compound of Formula 1 which is the product of the reaction, may be obtained in solid phase.
- the acid addition salt of the compound of Formula 1 may be obtained in solid form by filtration and drying.
- a method of preparing a compound of Formula 2 as represented above including: the step (b1) of preparing a compound of Formula 7 by introducing an amine protecting group X 1 into a compound of Formula 6; and the step (b2) of preparing the compound of Formula 2 by removing an azetidine nitrogen protecting group X 2 from the compound of Formula 7:
- the compound of Formula 2 may be an acid addition salt, wherein HA in Formula 2 is hydrochloric acid.
- the amine protecting group X 1 may protect a secondary amine group which does not belong to the nitrogen of the azetidine ring of the compound of Formula 7, when the compound of Formula 2 is prepared from the compound of Formula 7, i.e., in the reaction of the step (b2).
- the amine protecting group X 1 may be any protecting group capable of protecting a secondary amine group which is not included in the azetidine ring, in the preparation of the acid addition salt compound of Formula 2 by deprotection reaction of the azetidine nitrogen protecting group X 2 of the compound of Formula 7.
- the amine protecting group X 1 may be fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), or p-methoxybenzyl (PMB).
- a reagent capable of introducing the amine protecting group X 1 to the compound of Formula 6 may vary depending on a specific type of the amine protecting group X 1 .
- the reaction of the step (b1 ) may be carried out by reacting the compound of Formula 6 with a reagent selected from fluorenylmethoxycarbonyl chloride, trifluoroacetic acid anhydride, 4-methoxybenzyl chloride, and any combination thereof.
- the reaction of the step (b1 ) may be carried out in the presence of a base.
- the base may be any base as long as it does not inhibit the reaction of introducing the amine protecting group X 1 into the compound of Formula 6.
- the base may be a tertiary amine.
- the tertiary amine may be selected from diisopropylethylamine, triethylamine, N-methyl morpholine, and any combination thereof.
- the reaction of the step (b) may be carried out in the presence of both a reagent capable of introducing the amine protecting group X 1 , and a base.
- the reaction of the step (b) may be carried out in the presence of both a reagent selected from fluorenylmethoxycarbonyl chloride, trifluoroacetic acid anhydride, 4- methoxybenzyl chloride, and any combination thereof, and a base selected from diisopropylethylamine, triethylamine, N-methyl morpholine, and any combination thereof.
- a solvent used in the reaction of the step (b) is not limited to specific types as long as it does not inhibit the reaction.
- the solvent may be selected from acetonitrile, toluene, tetrahydrofuran, dichloromethane, chloroform, N,N- dimethylformamide, and any combination thereof.
- the reaction of the step (b1) may be carried out at a temperature of about -20 °C to a reflux temperature or less, and in some embodiments, at a temperature ranging from about -20 °C to about 120 °C, and in other embodiments, at a temperature ranging from about -10 °C to about 80 °C.
- the reaction of the step (b2) of preparing the compound of Formula 2, which is carried out after the reaction of the step (b1 ), may include the process of removing the azetidine nitrogen protecting group X 2 from the compound of Formula 7 and substituting the same with hydrogen instead.
- the azetidine nitrogen protecting group X 2 may be any protecting group which can be removed, leaving the amine protecting group X 1 not removed, and substituted with hydrogen.
- the azetidine nitrogen protecting group X 2 may be selected from the group consisting of butoxycarbonyl (Boc), tri phenyl methyl (Trt), and tetrahydropyranyl (THP).
- the azetidine nitrogen protecting group X 2 is butoxycarbonyl (Boc).
- the process of substitution with hydrogen in the step (b2) may be carried out at a temperature of about -20 °C to a reflux temperature, and in some embodiments, at a temperature ranging from about 0 °C to about 90 °C.
- the process of substitution with hydrogen in the reaction of the step (b2) may be carried out by reacting the compound of Formula 7 with an acid, thus removing the azetidine nitrogen protecting group X 2 from the compound of Formula 7, and substituting the same with hydrogen.
- the acid is not limited to specific types, and may be any acid capable of effectively removing the azetidine nitrogen protecting group X 2 , and forming the acid addition salt of Formula 2.
- the acid may be hydrohalogenic acid, for example, hydrochloric acid, hydrobromic acid, or hydroiodic acid.
- the acid may be an anhydrous hydrochloric acid or concentrated hydrochloric acid.
- a solvent used in the process of substitution with hydrogen in the reaction of the step (b2) may be any solvent which does not inhibit the corresponding reaction.
- the solvent may be selected from acetone, ethyl acetate, a C 1 -C 4 linear or branched alcohol, and any combination thereof.
- the acid and the solvent used in the reaction of the step (b2) may be, respectively, hydrochloric acid and acetone, or hydrochloric acid and ethyl acetate, or hydrochloric acid and isopropyl alcohol, or hydrochloric acid and ethanol, or hydrochloric acid and methanol.
- the acid addition salt of Formula 2 may be prepared by evaporation without a post- treatment process or by precipitation with addition of a suitable solvent, after the removal of X 2 from the compound of Formula 7 with addition of an acid into the solvent in the reaction of the step (b2) and the substitution with hydrogen instead.
- the suitable solvent added to precipitate the acid addition salt may be selected from ethylacetate, acetone, n- hexane, isopropyl alcohol, and any combination thereof, but is not limited thereto. Any suitable solvent may be selected by one of ordinary skill in the art in consideration of the required conditions for the solvent in the corresponding reaction.
- a hydrochloride salt among the acid addition salts of the compound of Formula 2 may be prepared by adding concentrated hydrochloric acid to the compound of Formula 7 in methanol and allowing a reaction to take place, concentrating the reaction product under reduced pressure, and then refluxing with addition of ethyl acetate, stirring at ambient temperature, and then filtering and drying.
- the compound of Formula 6 may be prepared by the step (b0) of reductive amination reaction of a compound represented by Formula 5:
- the reductive amination reaction of the compound of Formula 5 may be carried out by one of ordinary skill in the art based on the common knowledge known in the art.
- the compound of Formula 6 may be prepared with a high yield (see Synthesis 2011 , No.3, p. 490-496).
- the method of preparing the compound of Formula 1 may be represented by Reaction Scheme 3 below.
- the yield may be about 3 to 10 times, preferably, 5 to 8 times higher than that obtained in a known method, e.g., disclosed in US 9,682,973.
- the final product obtained in the present method may have at least 90%, preferably, at least 95%, more preferably, at least 97%, most preferably, at least 99% of purity (including 99.5% or 99.9%) when identified by the percent area of HPLC.
- one or more intermediates generated according to the present method may be obtained in a solid phase, thus resulting in more convenient separation of the intermediates.
- the reaction to generate intermediates is completed and the generation of related materials is low, and thus there is no need to perform column chromatography, which was previously needed for separation and purification. Due to the reduction in the generation of related materials and easy separation of the intermediates, a final product may be obtained with high yield.
- column chromatography which is a process not suitable for mass (e.g., large-scale and commercial) production, may be avoided, and quality reproducibility may be improved, and thus the method may be advantageously applied to mass production.
- the amine protecting group X 1 may be selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB), but is not limited thereto.
- HA may be any acid which forms an acid addition salt.
- HA may be a hydrohalogenic acid.
- the hydroha logenic acid may be hydrochloric acid, hydrobromic acid, or hydroiodic acid, and, for example, may be hydrochloric acid.
- the compound of Formula 2 is a novel intermediate compound in solid phase, which was not used in existing methods for the preparation of the compound of Formula 1 , or a pharmaceutical acceptable salt thereof, as described above.
- the compound of Formula 2 is used as an intermediate, all the products of the subsequent steps, including the intermediate, can be obtained in a solid phase. Purification steps may then be minimized, which results in a method for preparing the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, with high yield and high purity. Therefore, the compound of Formula 1 , or a pharmaceutically acceptable salt, thereof may be mass (e.g., large-scale and commercial) produced with high yield and high purity.
- the compound of Formula 2 may be selected from the group consisting of the following compounds: (9H-fluorene-9-yl)methyl(azetidin-3-ylmethyl)(cyclopropyl)carbamate hydrochloride of Formula 2a,
- a compound of Formula 4 [Formula 4] wherein X 1 is an amine protecting group.
- the amine protecting group X 1 may be selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB), but is not limited thereto.
- the compound of Formula 4 is a novel intermediate compound in solid phase, which was not used in existing methods for the preparation of the compound of Formula 1 , or a pharmaceutical acceptable salt thereof, as described above.
- the compound of Formula 4 may be used as an intermediate, the compound of Formula 1 may be obtained in a solid phase. Purification steps may then be minimized, which results in a method of preparing the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, with high yield and high purity. Therefore, the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, may be produced on mass (e.g., large-scale and commercial) produced with high yield and high purity.
- the compound of Formula 4 may be selected from the group consisting of the following compounds:
- a compound of Formula 7 [Formula 7] wherein X 1 is an amine protecting group, and X 2 is an azetidine nitrogen protecting group.
- the amine protecting group X 1 may be selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB), but is not limited thereto.
- the azetidine nitrogen protecting group X 2 may be selected from the group consisting of butoxycarbonyl (Boc), triphenylmethyl (Trt), and tetrahydropyranyl (THP). In one embodiment, the azetidine nitrogen protecting group X 2 may be butoxycarbonyl (Boc).
- the compound of Formula 7 is a novel intermediate compound, which was not used in existing methods for the preparation of the compound of Formula 1 , or a pharmaceutical acceptable salt thereof, as described above.
- the compound of Formula 7 may be selected from the group consisting of the following compounds: tert-butyl 3-([([(9H-fluorene-9-yl)methoxy]carbonyl)(cyclopropyl) ami nojmethyl )azetidin- 1 -carboxylate of Formula 7a,
- the methods of the present invention are used to prepare a drug substance, pharmaceutical composition, or medicament comprising the compound of Formula 1 , or a pharmaceutically acceptable salt thereof.
- the intermediate compounds described herein may be present as an impurity.
- the amount of each of the compounds of Formulas 2 to 7, when present as an impurity may be controlled to be present at trace levels, for example, to be not more than about 1.0% or less, about 0.5% or less, about 0.2% or less, about 0.1 % or less, of the drug substance, or to be not present at all.
- substantially pure forms of the compound of Formula 1 prepared by the methods of the present invention are provided for use as a drug substance in the preparation of a pharmaceutical composition or medicament.
- the present invention encompasses pharmaceutical compositions comprising substantially pure drug substance, wherein the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, is present in the drug substance in an amount greater than about 90%, about 95%, about 97%, about 99%, about 99.5%, or about 99.9%.
- Percent purity may be determined using well-known methods in the art. For example, percent purity may be determined by reference to the percentage of measured peak area from the sum of peak area of all peaks under suitable chromatography (e.g., HPLC) detection conditions.
- the present invention therefore provides pharmaceutical compositions comprising an effective amount of a compound of Formula 1 , or a pharmaceutically acceptable salt thereof, as an active ingredient, wherein said compound is prepared from the methods of the present invention (e.g., one or more of the intermediates described herein and Reaction Scheme 1 and Reaction Scheme 2).
- the pharmaceutical compositions of the invention may be administered in patients to treat cancers, including cancers sensitive to PARP inhibitors.
- Such formulations may include binders, fillers, disintegrants, lubricants, coloring agents and preservatives, and other pharmaceutically acceptable excipients.
- the present invention provides a product comprising a compound of Formula 1 ,
- reaction mixture was stirred at ambient temperature for 1 hour, 300 mL of water was added thereto to wash the organic layer, and then the organic layer was washed with a 1N hydrochloric acid aqueous solution and a 1N sodium carbonate aqueous solution.
- the organic layer was washed with a 5% sodium chloride aqueous solution, treated with 10.0 g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure.
- 300 mL of toluene was added to the residue, stirred at ambient temperature overnight, filtered, and then dried at 50 °C, to thereby yield 47.0 g of compound 4c (Yield: 81.2%).
- the filtrate was adjusted to pH 9 or greater with a 1 N sodium hydroxide solution and extracted by adding 300 mL of dichloromethane.
- the aqueous layer was further extracted by adding 300 mL of dichloromethane thereto, and then the organic layer was mixed therewith, washed with a 5% sodium chloride aqueous solution, and then concentrated.
- 80 mL of methanol and 40 mL of dichloromethane were added to the residue, and then 150 mL of acetone was slowly added thereto.
- the resulting solid was stirred at ambient temperature overnight, filtered, and dried at 40 °C to yield 17.5 g of compound 1 (Yield: 90.1%).
- the aqueous layer was further washed with 100 mL of dichloromethane, adjusted to pH 9 or greater with a 1 N sodium hydroxide aqueous solution, and then extracted with 100 mL of dichloromethane.
- the aqueous layer was further extracted with 100 mL of dichloromethane, and the organic layer was mixed therewith, washed with a 5% sodium chloride aqueous solution and then concentrated.
- 60 mL of methanol and 30 mL of dichloromethane were added to the residue, and 120 mL of acetone was slowly added thereto.
- the resulting solid was stirred at ambient temperature overnight, filtered, and dried at 40 °C, to thereby yield 13.4 g of compound 1 (Yield: 86.9%).
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Abstract
The present application provides a method of preparing 4-[3-{3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, or a pharmaceutically acceptable sail thereof, intermediates in the preparation thereof, methods of preparing the intermediates, and compositions and products comprising said compound made from the methods that result in high purity and yield.
Description
PROCESS FOR PREPARING A PHTHALAZINONE DERIVATIVE AND INTERMEDIATES THEREOF
[CROSS REFERENCE TO RELATED APPLICATION]
This application claims priority to US Serial No. 63/013,310, filed 21 April 2020, the content of which is incorporated herein by reference in its entirety.
[Technical Field]
The present invention relates to methods of preparing phthalazinone derivatives which are poly (ADP-ribose) polymerase (PARP) inhibitors, intermediates used in these preparation methods, methods of preparing the intermediates, and compositions and products comprising said derivatives prepared from methods that result in high purity and yield.
[Background Art of Invention]
Patent document 1 (US 9,682,973) discloses phthalazinone derivatives having anti-cancer activity as poly( ADP-ribose) polymerase (PARP) inhibitors, racemates, enantiomers or diastereomers thereof, or pharmaceutically acceptable salts thereof.
The patent document discloses methods of preparing the phthalazinone derivatives, and in particular, in Examples 143 and 171, methods of preparing 4-[3-(3- [(cyclopropylamino)methyl]azetidine-1 -carbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one, or a pharmaceutically acceptable salt thereof, as represented in Reaction Scheme 1 below. [Reaction Scheme 1]
When 4-[3-(3-[(cyclopropylamino)methyl] azetidine- 1 -carbony l)-4-fl uorobenzyl] phthalazin-1 (2H)-one, or a pharmaceutically acceptable salt thereof, is prepared according to the preparation method above, in each step, the reaction does not run to completion, resulting in a final product with a very low total yield relative to the starting materials. In addition, due to the generation of a plurality of impurities, purification through column chromatography is necessary. In addition, since most of the prepared intermediates are present in the liquid phase, it is difficult to achieve a quantitative reaction at each step, and application to mass (e.g., large-scale and commercial) production is difficult due to poor quality reproducibility.
In particular, in the synthesis process of 4-[3-(3- [(cyclopropyla m ino)methy IJazetid in e- 1 -carbonyl )-4-fl uorobenzyl] phthalazin-1 (2H)-one
(Example 143, Step 2), the reaction is not completed even when the reaction proceeds for 24 hours or longer. Further, due to the generation of a plurality of related materials, an additional purification step, including column chromatography, is necessary to obtain substantially pure sample, which diminishes the final yield.
[Prior Art Document]
[Patent Document]
(Patent document 0001 ) US 9,682,973
[Disclosure]
[Technical Problem]
An aspect of the present invention is to provide a method of preparing 4-[3-(3- [(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one, or a pharmaceutically acceptable salt thereof, where one or more intermediates are obtained in a solid phase, and where the reduction in the formation of impurities avoids the need for an additional purification step, thereby increasing the total yield in a manner that is suitable for mass (e.g., large-scale and commercial) production.
Another aspect is to provide one or more novel intermediates which can be used in the above-described preparation method.
Another aspect is to provide a method of preparing the one or more intermediates.
Compositions and products containing the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, prepared from the methods of the present invention are also provided.
Other objectives and advantages of the present invention will become apparent from the following detailed descriptions along with the appended drawings. The contents not described in the present specification may be sufficiently recognized and inferred by those skilled in the art or similar fields of the present invention, and thus description thereof is omitted.
[Technical Solution]
According to an aspect of the present invention, there is provided a method of preparing a compound of Formula 1 , or a pharmaceutically acceptable salt thereof:
[Formula 1j
the method comprising a step (a2) of deprotecting a compound of Formula 4 to prepare the compound of Formula 1 :
[Formula 4]
wherein X1 is an amine protecting group.
According to another aspect of the present invention, there is provided a method of preparing a compound of Formula 4, comprising a step (a1) of reacting a compound of Formula 2 with a compound of Formula 3:
[Formula 2]
wherein, X1 is an amine protecting group, and HA is an acid which forms an acid addition salt; and
[Formula 3]
According to another aspect of the present invention, there is provided a method of preparing a compound of Formula 2,
[Formula 2]
the method comprising: a step (b1) of introducing an amine protecting group X1 into a compound of Formula 6 to prepare a compound of Formula 7; and a step (b2) of removing an azetidine nitrogen protecting group X2 from the compound of Formula 7 to prepare the compound of Formula 2:
[Formula 6]
[Formula 7]
wherein, X1 is an amine protecting group,
X2 is an azetidine nitrogen protecting group, and HA is an acid which forms an acid addition salt.
According to another aspect of the present invention, there is provided a compound of Formula 2:
[Formula 2]
wherein, X1 is an amine protecting group,
HA is an acid which forms an acid addition salt.
According to another aspect of the present invention, there is provided a compound of Formula 4:
[Formula 4]
wherein X1 is an amine protecting group.
According to another aspect of the present invention, there is provided a compound of Formula 7:
[Formula 7]
wherein, X1 is an amine protecting group, and X2 is an azetidine nitrogen protecting group.
[Effect of the Invention]
According to an aspect of the present invention, one or more intermediates generated according to the present method may be obtained in a solid phase, thus
resulting in more convenient separation of the intermediates. In each process, the reaction to generate intermediates may be completed with minimal side reactions, and low levels of impurities, and thus there is no need to perform column chromatography, which was previously needed for separation and purification to obtain substantially pure compound. Due to the reduction in the generation of impurities and easy separation of the intermediates, a final product may be obtained with high purity and high yield. Therefore, the preparation method according to an aspect of the present invention may prepare 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4- fluorobenzyl]phthalazin-1 (2H)-one, or a pharmaceutically acceptable salt thereof, with higher purity and higher yield, and more economically, and thus is suitable for mass ( e.g ., large-scale and commercial) production.
[Detailed Description of the Invention]
Hereinafter, the present invention will be described in greater detail.
Unless otherwise defined, all technical terms used in the present invention have the same meanings as commonly understood by those skilled in the related art of the present invention. In addition, although a preferred method or example is described in the specification, those similar or equivalent thereto fall within the scope of the present invention. In addition, the term "comprising" is intended to have an inclusive meaning and permits the inclusion of additional elements other than the listed elements.
Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth as used in the specification and claims are to be understood as being modified in all instances by the term "about."
As used herein, the term "compound of Formula" is not intended to be limited to the Formula. When one structure is illustrated, unless stated otherwise, it is understood that all possible stereoisomers and tautomers thereof are included.
The term "protecting group" refers to a functional group which protects, from unintentional reaction, a functional group such as an amino group or alcohol group, by
being bonded thereto via a covalent bond, and allows the functional group to be regenerated (i.e., de-protected) after treatment of the protecting group with a suitable reagent.
As used herein, the term "intermediates generated according to the present method are obtained in a solid phase" means that the intermediates are obtained in a solid form by, for example, filtration and drying, or similar steps known in the art.
The term "ambient temperature" refers to an indoor ambient temperature in the range of about 1 °C to about 30 °C.
The contents of all publications cited as reference documents herein are incorporated in the present specification by reference in their entirety.
Explanations and embodiments disclosed in the present invention may be applied to other explanations and embodiments, respectively. That is, all combinations of various elements disclosed in the present invention belong to the scope of the present invention. Additionally, the scope of the present invention should not be limited by the specific descriptions described herein below.
An aspect of the present invention provides a method of preparing a compound of Formula 1 , or a pharmaceutically acceptable salt thereof,
[Formula 1]
the method including a step (a2) of deprotecting a compound of Formula 4 to prepare the compound of
Formula 1 :
[Formula 4]
The compound of Formula 4 may be prepared by a step (a1 ) of reacting a compound of Formula 2 with a compound of Formula 3:
[Formula 2]
wherein X1 is an amine protecting group, and HA is an acid which forms an acid addition salt;
[Formula 3]
Another aspect of the present invention provides a method of preparing a compound of Formula 4, including a step (a1) of reacting a compound of Formula 2 with a compound of Formula 3:
[Formula 2]
[Formula 3]
wherein
X1 is an amine protecting group, and HA is an acid which forms an acid addition salt.
HA, as shown above, may be any acid which forms an acid addition salt. For example, the acid addition salt may be a hydrohalogenic acid salt. The hydroha logenic acid may include hydrochloric acid (HCI), hydrobromic acid (HBr), or hydroiodic acid (HI), and preferably, hydrochloric acid (HCI).
In the step (a1), the compound of Formula 4 may be obtained by amide bond between the compound of Formula 2 and the compound of Formula 3. In the step (a2), the compound of Formula 1 may be obtained by removing X1 which is a protecting group for the amine group of the compound of Formula 4.
In one embodiment, the method of preparing the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, may be represented by Reaction Scheme 2 below.
[Reaction Scheme 2]
The compound of Formula 3 used in the step (a1) may be prepared according to any method known in the art, for example, a method disclosed in WO 2004/080976 (see section b in "Synthesis of Key Intermediates”).
In one embodiment, the compound of Formula 2 may be in the form of hydrochloride salt wherein HA is hydrochloric acid. X1 may be any amine protecting group capable of protecting the amine group to which X1 is bonded in the reaction of step (a1 ). This amine protecting group may include, but is not limited to, fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), or p-methoxy benzyl (PMB).
The step (a1) of preparing the compound of Formula 4 may be carried out under any condition which allows formation of amide bond between the azetidine amine of the compound of Formula 2 and the carboxyl group of the compound of Formula 3.
In one embodiment, the step (a1 ) may be carried out in the presence of an amide coupling reagent. The amide coupling reagent refers to a reagent which activates a carboxyl group of a reactant to be able to form an amide group during reaction with an amine. The amide coupling reagent may include, but not limited to, trimethylacetyl chloride, 1 ,T-carbonyldi imidazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDC), or any combination thereof.
The step (a1) may be carried out in the presence of a base, for example, in the presence of at least one base selected from the group consisting of diisopropylethylamine, triethylamine, N-methy I morpholine, and any combination thereof.
In one embodiment, the step (a1 ) may be carried out in the presence of both at least one amide coupling reagent and at least one base.
In one embodiment, the step (a1 ) may be carried out in the presence of both at least one amide coupling agent selected from the group consisting of trimethylacetyl chloride, 1 ,T-carbonyldi imidazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDC), and any combination thereof, and at least one base selected from the group consisting of diisopropylethylamine, triethylamine, N-methylmorpholine, and any combination thereof.
For the reaction in the step (a1), a solvent which does not inhibit the reaction may be used. For example, the solvent may be selected from acetonitrile, acetone, toluene, tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide, and any combination thereof. In one embodiment, the solvent may be toluene.
The reaction in the step (a1 ) may be carried out at a temperature of about -20 °C to a reflux temperature, and in some embodiments, at about -20 °C to about 120 °C, and in other embodiments, about -10 °C to about 40 °C.
In the step (a1 ), the compound of Formula 4, which is the product of the reaction, may be obtained in solid phase. Thus, the compound of Formula 4 may be obtained in solid form by filtration and drying.
The step (a2) of preparing the compound of Formula 1 is a reaction of removing the amine protecting group X1 from the compound of Formula 4, and the reaction conditions for removing the amine protecting group X1 may vary depending on the type of the amine protecting group X1.
In one embodiment, the step (a2) of preparing the compound of Formula 1 may include, when X1 is fluorenylmethoxycarbonyl (Fmoc), reacting the compound of Formula 4 with a non-nucleophilic base. The non-nucleophilic base is not limited to specific types, and may be any non-nucleophilic base which can effectively remove the amine protecting group X1. For example, the non-nucleophilic base may be selected from piperidine, diisopropylethylamine, 1 ,8-diazabicyclo[5,4,0]undec-7-ene, and any combination thereof. In this case, a solvent for the reaction in the step (a2) may be acetonitrile, tetrahydrofuran, N,N-dimethylformamide, or any combination thereof. For example, when X1 is fluorenylmethoxycarbonyl (Fmoc), the non-nucleophilic base and the solvent may be, respectively, piperidine and acetonitrile, diisopropylethylamine and tetrahydrofuran, or 8- diazabicyclo[5,4,0]undec-7-ene and N,N-dimethylfomnamide.
In another embodiment, in the step (a2), when X1 is trifluoroacetyl (Tfa), the compound of Formula 4 may be reacted with an alkali base. The alkali base is not limited to specific types, and may be any alkali base which can effectively separate the amine protecting group X1. For example, the alkali base may be potassium hydroxide, potassium carbonate, sodium hydroxide, sodium carbonate, or any combination thereof. In this case, a solvent for the reaction in the step (a2) may be a solvent in which water is added to a C1-C4 linear alcohol, a C1-C4 branched alcohol, or any combination thereof. For example, when X1 is trifluoroacetyl (Tfa), the alkali base and the solvent may be, respectively, potassium hydroxide and isopropyl alcohol/water, potassium carbonate and
methanol/water, sodium hydroxide and methanol/ water, or sodium carbonate and ethanol/water.
In still another embodiment, in the step (a2), when X1 is p-methoxy benzyl (PMB), the compound of Formula 4 may be reacted with an acid. The acid is not limited to specific types, and may be any acid which can effectively remove the amine protecting group. For example, trif!uoroacetic acid may be used as the reagent and a solvent. In this case, in the reaction of the step (2), a ratio (w/v) of the weight of the compound of Formula 4 and the volume of trifluoroacetic acid may be about 1 :5 to about 1 :40. For example, when X1 is p-methoxybenzyl (PMB), a ratio (w/v) of the compound of Formula 4 to trifluoroacetic acid, which are used in the reaction of the step (a2), may be about 1:10.
In the step (a2), the compound of Formula 1 , which is the product of the reaction, may be obtained in solid phase. Thus, the compound of Formula 1 may be obtained in solid form by filtration and drying.
A step (a3) of preparing an acid addition salt of the compound of Formula 1 by reacting the compound of Formula 1 with an acid may be further performed to thereby prepare a pharmaceutically acceptable salt of the compound of Formula 1. The preparing of an acid addition salt of the compound of Formula 1 may be performed using a suitable method by those skilled in the art based on the common knowledge in the field of organic chemistry. The acid addition salt of the compound of Formula 1 may be any pharmaceutically acceptable acid addition salt, for example, an acid addition salt formed from a free acid. The free acid may be an inorganic acid or an organic acid. The inorganic acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid. The organic acid may be, but not limited to, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, adipic acid, L- or D-tartaric acid, DL-tartaric acid, citric acid, lactic acid, benzoic acid, mandelic acid, salicylic acid, cinnamic acid, methane sulfonic acid, ethane sulfonic acid, p-toluene sulfonic acid, glycolic acid, pyruvic acid, glucuronic acid, glutamic acid, aspartic acid, or any combination thereof.
In one embodiment, the acid addition salt may be an inorganic acid addition salt, and in an embodiment, a hydrochloric acid addition salt. The reaction in the step (a) of preparing an acid addition salt of the compound of Formula 1 may be carried out in any
solvent which does not inhibit formation of the acid addition salt. For example, the solvent may be selected from alcohol, ketone, ether, acetic acid esters, dichloromethane, chloroform, and any combination thereof, and in some embodiments, may be a C1-C5 alcohol, a C3-C10 ketone, a C2-C10 ether, C2-C4 alkyl acetate, dichloromethane, chloroform, or any combination thereof.
The reaction in the step (a3) may be carried out at a temperature of about -20 °C to a reflux temperature, and in some embodiments, at a temperature ranging from about -20°C to about 50 °C, and in other embodiments, at a temperature ranging from about - 10°C to about 30 °C.
In one embodiment, a hydrochloride of the compound of Formula 1 may be prepared by adding, at a temperature ranging from about -20 °C to a reflux temperature, anhydrous hydrochloric acid or concentrated hydrochloric acid to the compound represented by Formula 1 , with a solvent of an alcohol, a mixture of alcohol and ketone, a mixture of alcohol and dichloromethane, a mixture of alcohol and chloroform, a mixture of alcohol and ether, or a mixture of alcohol and acetic acid esters. For example, the alcohol, the ketone, the ether, and the acetic acid esters may be, respectively, a C1-C5 alcohol, a C3-C10 ketone, a C2-C10 ether, and C2-C4 alkyl acetate.
In one embodiment, a hydrochloride of the compound of Formula 1 may be prepared by adding, at a temperature ranging from about -20 °C to a reflux temperature or less, anhydrous hydrochloric acid or concentrated hydrochloric acid to the compound represented by Formula 1 , with a solvent of an alcohol, a mixture of alcohol and ketone, a mixture of alcohol and dichloromethane, a mixture of alcohol and chloroform, or a mixture of alcohol and ether, and then filtering and drying the thus-formed solid. For example, the alcohol, the ketone, and the ether may be, respectively, a C1-C5 alcohol, a C3-C10 ketone, and a C2-C10 ether.
In the step (a3), the acid addition salt of the compound of Formula 1, which is the product of the reaction, may be obtained in solid phase. Thus, the acid addition salt of the compound of Formula 1 may be obtained in solid form by filtration and drying.
In another aspect, there is provided a method of preparing a compound of Formula 2 as represented above,
the method including: the step (b1) of preparing a compound of Formula 7 by introducing an amine protecting group X1 into a compound of Formula 6; and the step (b2) of preparing the compound of Formula 2 by removing an azetidine nitrogen protecting group X2 from the compound of Formula 7:
[Formula 6]
[Formula 7]
wherein, in the above Formula, X1 is an amine protecting group, and X2 is an azetidine nitrogen protecting group.
In one embodiment, the compound of Formula 2 may be an acid addition salt, wherein HA in Formula 2 is hydrochloric acid.
In the reaction of the step (b1 ) of preparing the compound of Formula 7 by introducing an amine protecting group X1 into the compound of Formula 6, the amine protecting group X1 may protect a secondary amine group which does not belong to the nitrogen of the azetidine ring of the compound of Formula 7, when the compound of Formula 2 is prepared from the compound of Formula 7, i.e., in the reaction of the step (b2). Accordingly, the amine protecting group X1 may be any protecting group capable of protecting a secondary amine group which is not included in the azetidine ring, in the preparation of the acid addition salt compound of Formula 2 by deprotection reaction of the azetidine nitrogen protecting group X2 of the compound of Formula 7. For example, the amine protecting group X1 may be fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), or p-methoxybenzyl (PMB).
In the reaction of the step (b1 ), a reagent capable of introducing the amine protecting group X1 to the compound of Formula 6 may vary depending on a specific type of the amine protecting group X1. For example, the reaction of the step (b1 ) may be carried out by reacting the compound of Formula 6 with a reagent selected from fluorenylmethoxycarbonyl chloride, trifluoroacetic acid anhydride, 4-methoxybenzyl chloride, and any combination thereof.
The reaction of the step (b1 ) may be carried out in the presence of a base. The base may be any base as long as it does not inhibit the reaction of introducing the amine protecting group X1 into the compound of Formula 6. For example, the base may be a tertiary amine. For example, the tertiary amine may be selected from diisopropylethylamine, triethylamine, N-methyl morpholine, and any combination thereof.
In one embodiment, the reaction of the step (b) may be carried out in the presence of both a reagent capable of introducing the amine protecting group X1, and a base. For example, the reaction of the step (b) may be carried out in the presence of both a reagent selected from fluorenylmethoxycarbonyl chloride, trifluoroacetic acid anhydride, 4- methoxybenzyl chloride, and any combination thereof, and a base selected from diisopropylethylamine, triethylamine, N-methyl morpholine, and any combination thereof.
A solvent used in the reaction of the step (b) is not limited to specific types as long as it does not inhibit the reaction. For example, the solvent may be selected from acetonitrile, toluene, tetrahydrofuran, dichloromethane, chloroform, N,N- dimethylformamide, and any combination thereof.
The reaction of the step (b1) may be carried out at a temperature of about -20 °C to a reflux temperature or less, and in some embodiments, at a temperature ranging from about -20 °C to about 120 °C, and in other embodiments, at a temperature ranging from about -10 °C to about 80 °C.
The reaction of the step (b2) of preparing the compound of Formula 2, which is carried out after the reaction of the step (b1 ), may include the process of removing the azetidine nitrogen protecting group X2 from the compound of Formula 7 and substituting the same with hydrogen instead. The azetidine nitrogen protecting group X2 may be any protecting group which can be removed, leaving the amine protecting group X1 not
removed, and substituted with hydrogen. For example, the azetidine nitrogen protecting group X2 may be selected from the group consisting of butoxycarbonyl (Boc), tri phenyl methyl (Trt), and tetrahydropyranyl (THP). In one embodiment, the azetidine nitrogen protecting group X2 is butoxycarbonyl (Boc).
The process of substitution with hydrogen in the step (b2) may be carried out at a temperature of about -20 °C to a reflux temperature, and in some embodiments, at a temperature ranging from about 0 °C to about 90 °C.
For example, the process of substitution with hydrogen in the reaction of the step (b2) may be carried out by reacting the compound of Formula 7 with an acid, thus removing the azetidine nitrogen protecting group X2 from the compound of Formula 7, and substituting the same with hydrogen. The acid is not limited to specific types, and may be any acid capable of effectively removing the azetidine nitrogen protecting group X2, and forming the acid addition salt of Formula 2. For example, the acid may be hydrohalogenic acid, for example, hydrochloric acid, hydrobromic acid, or hydroiodic acid. In one embodiment, the acid may be an anhydrous hydrochloric acid or concentrated hydrochloric acid.
A solvent used in the process of substitution with hydrogen in the reaction of the step (b2) may be any solvent which does not inhibit the corresponding reaction. For example, when the azetidine nitrogen protecting group X2 is butoxycarbonyl (Boc), the solvent may be selected from acetone, ethyl acetate, a C1-C4 linear or branched alcohol, and any combination thereof.
In one embodiment, when X2 is butoxycarbonyl (Boc), the acid and the solvent used in the reaction of the step (b2) may be, respectively, hydrochloric acid and acetone, or hydrochloric acid and ethyl acetate, or hydrochloric acid and isopropyl alcohol, or hydrochloric acid and ethanol, or hydrochloric acid and methanol.
The acid addition salt of Formula 2 may be prepared by evaporation without a post- treatment process or by precipitation with addition of a suitable solvent, after the removal of X2 from the compound of Formula 7 with addition of an acid into the solvent in the reaction of the step (b2) and the substitution with hydrogen instead. The suitable solvent added to precipitate the acid addition salt may be selected from ethylacetate, acetone, n-
hexane, isopropyl alcohol, and any combination thereof, but is not limited thereto. Any suitable solvent may be selected by one of ordinary skill in the art in consideration of the required conditions for the solvent in the corresponding reaction.
In one embodiment, a hydrochloride salt among the acid addition salts of the compound of Formula 2, may be prepared by adding concentrated hydrochloric acid to the compound of Formula 7 in methanol and allowing a reaction to take place, concentrating the reaction product under reduced pressure, and then refluxing with addition of ethyl acetate, stirring at ambient temperature, and then filtering and drying.
The compound of Formula 6 may be prepared by the step (b0) of reductive amination reaction of a compound represented by Formula 5:
[Formula 5]
wherein, in Formula 5, X2 is an azetidine nitrogen protecting group.
In the reaction of the step (b0), the reductive amination reaction of the compound of Formula 5 may be carried out by one of ordinary skill in the art based on the common knowledge known in the art. In one embodiment, in the reaction of the step (b0), by proceeding with the reductive amination using trifluoroethanol as a solvent and sodium borohydride without a catalyst or an additive, the compound of Formula 6 may be prepared with a high yield (see Synthesis 2011 , No.3, p. 490-496).
In one embodiment, the method of preparing the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, may be represented by Reaction Scheme 3 below.
[Reaction Scheme 3]
According to an exemplary preparation method of the present invention, e.g., represented in Reaction Scheme 3, 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1- carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, or a pharmaceutically acceptable salt thereof, can be prepared with higher purity and higher yield. In one embodiment, the yield may be about 3 to 10 times, preferably, 5 to 8 times higher than that obtained in a known method, e.g., disclosed in US 9,682,973. In another embodiment, the final product obtained in the present method may have at least 90%, preferably, at least 95%, more preferably, at least 97%, most preferably, at least 99% of purity (including 99.5% or 99.9%) when identified by the percent area of HPLC.
In the method of preparing the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, according to an aspect of the present invention, one or more intermediates generated according to the present method (for example, a compound of Formula 2 or 4) may be obtained in a solid phase, thus resulting in more convenient separation of the intermediates. In each process, the reaction to generate intermediates is completed and the generation of related materials is low, and thus there is no need to perform column chromatography, which was previously needed for separation and
purification. Due to the reduction in the generation of related materials and easy separation of the intermediates, a final product may be obtained with high yield. In addition, since column chromatography, which is a process not suitable for mass (e.g., large-scale and commercial) production, may be avoided, and quality reproducibility may be improved, and thus the method may be advantageously applied to mass production.
In another aspect, there is provided a compound of Formula 2:
[Formula 2]
wherein, in Formula 2, X1 is an amine protecting group, and HA is an acid which forms an acid addition salt.
The amine protecting group X1 may be selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB), but is not limited thereto.
HA may be any acid which forms an acid addition salt. For example, HA may be a hydrohalogenic acid. The hydroha logenic acid may be hydrochloric acid, hydrobromic acid, or hydroiodic acid, and, for example, may be hydrochloric acid.
The compound of Formula 2 is a novel intermediate compound in solid phase, which was not used in existing methods for the preparation of the compound of Formula 1 , or a pharmaceutical acceptable salt thereof, as described above. When the compound of Formula 2 is used as an intermediate, all the products of the subsequent steps, including the intermediate, can be obtained in a solid phase. Purification steps may then be minimized, which results in a method for preparing the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, with high yield and high purity. Therefore, the compound of Formula 1 , or a pharmaceutically acceptable salt, thereof may be mass (e.g., large-scale and commercial) produced with high yield and high purity.
In one embodiment, the compound of Formula 2 may be selected from the group consisting of the following compounds:
(9H-fluorene-9-yl)methyl(azetidin-3-ylmethyl)(cyclopropyl)carbamate hydrochloride of Formula 2a,
[Formula 2a]
N-(azetidin-3-ylmethyl)-N-cyclopropyl-2,2,2-trifluoroacetamide hydrochloride of
Formula 2b,
[Formula 2b]
N-(azetidin-3-ylmethyl)-N'-(4-methoxybenzyl)cyclopropanamine hydrochloride of Formula 2c,
[Formula 2c]
In another aspect, there is provided a compound of Formula 4: [Formula 4]
wherein X1 is an amine protecting group.
The amine protecting group X1 may be selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB), but is not limited thereto.
The compound of Formula 4 is a novel intermediate compound in solid phase, which was not used in existing methods for the preparation of the compound of Formula 1 , or a pharmaceutical acceptable salt thereof, as described above. When the compound of Formula 4 is used as an intermediate, the compound of Formula 1 may be obtained in a solid phase. Purification steps may then be minimized, which results in a method of preparing the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, with high yield and high purity. Therefore, the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, may be produced on mass (e.g., large-scale and commercial) produced with high yield and high purity.
In one embodiment, the compound of Formula 4 may be selected from the group consisting of the following compounds:
(9H-fluorene-9-yl)methyl cyclopropyl([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin- 1 -yl )methyl]benzoyl )azetidin-3-y IJmethyl )carba mate of Formula 4a,
[Formula 4a]
N-cyclopropyl-2,2,2-trifluoro-N'-([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1- yl)methyl]benzoyl)azetidin-3-yl]methyl)acetamide of Formula 4b,
[Formula 4b]
4-(3-[3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidin-1-carbonyl]-4- fluorobenzyl)phthalazin-1(2H)-one of Formula 4c,
[Formula 4c]
In another aspect, there is provided a compound of Formula 7: [Formula 7]
wherein X1 is an amine protecting group, and X2 is an azetidine nitrogen protecting group.
The amine protecting group X1 may be selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB), but is not limited thereto.
The azetidine nitrogen protecting group X2 may be selected from the group consisting of butoxycarbonyl (Boc), triphenylmethyl (Trt), and tetrahydropyranyl (THP). In one embodiment, the azetidine nitrogen protecting group X2 may be butoxycarbonyl (Boc).
The compound of Formula 7 is a novel intermediate compound, which was not used in existing methods for the preparation of the compound of Formula 1 , or a pharmaceutical acceptable salt thereof, as described above.
In one embodiment, the compound of Formula 7 may be selected from the group consisting of the following compounds: tert-butyl 3-([([(9H-fluorene-9-yl)methoxy]carbonyl)(cyclopropyl) ami nojmethyl )azetidin- 1 -carboxylate of Formula 7a,
[Formula 7a]
tert-butyl 3-[(cyclopropyl-2,2,2-trifluoroacetamido)methyl] azetidin-1 -carboxylate of Formula 7b,
[Formula 7b]
terf-butyl 3-([cyclopropy l(4-methoxybenzyl)amino]methyl)azetid in- 1 -carboxylate of Formula 7c,
[Formula 7c]
In another aspect of the invention, the methods of the present invention are used to prepare a drug substance, pharmaceutical composition, or medicament comprising the compound of Formula 1 , or a pharmaceutically acceptable salt thereof. When the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, is used as a drug substance, the intermediate compounds described herein may be present as an impurity. The amount of each of the compounds of Formulas 2 to 7, when present as an impurity, may be controlled to be present at trace levels, for example, to be not more than about 1.0% or less, about 0.5% or less, about 0.2% or less, about 0.1 % or less, of the drug substance, or to be not present at all.
Thus, in one aspect, substantially pure forms of the compound of Formula 1 prepared by the methods of the present invention are provided for use as a drug substance in the preparation of a pharmaceutical composition or medicament. In one embodiment, the present invention encompasses pharmaceutical compositions comprising substantially pure drug substance, wherein the compound of Formula 1 , or a pharmaceutically acceptable salt thereof, is present in the drug substance in an amount greater than about 90%, about 95%, about 97%, about 99%, about 99.5%, or about 99.9%. Percent purity may be determined using well-known methods in the art. For example, percent purity may be determined by reference to the percentage of measured peak area from the sum of peak area of all peaks under suitable chromatography (e.g., HPLC) detection conditions.
In one aspect, the present invention therefore provides pharmaceutical compositions comprising an effective amount of a compound of Formula 1 , or a pharmaceutically acceptable salt thereof, as an active ingredient, wherein said compound is prepared from the methods of the present invention (e.g., one or more of the intermediates described herein and Reaction Scheme 1 and Reaction Scheme 2). The pharmaceutical compositions of the invention may be administered in patients to treat cancers, including cancers sensitive to PARP inhibitors. Such formulations may include binders, fillers, disintegrants, lubricants, coloring agents and preservatives, and other pharmaceutically acceptable excipients.
In another non-limiting embodiment, the present invention provides a product comprising a compound of Formula 1 ,
[Formula 1]
or a pharmaceutically acceptable salt thereof, wherein the compound of Formula 1 , or the pharmaceutically acceptable salt thereof, is produced by the methods of the present invention described above, as for example, illustrated in Reaction Scheme 2 and Reaction Scheme 3.
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are for illustrative purposes only, and the invention is not intended to be limited by these Examples.
Example 1 :
Preparation of tert-butyl 3-[(cyclopropylamino)methyl]azetidin-1- carboxylate (Formula 6a)
10 kg of tert- butyl 3-formylazetidin- 1 -ca rboxylate was added into a reactor, and 6.5 kg of trifluoroethanol was added thereto. 0.3 kg of cyclopropylamine was added at
0 °C, stirring at ambient temperature for 1 hour, followed by cooling the reactor down to 0 °C. 0.2 kg of sodium borohydride was slowly added and stirred at ambient temperature
for 1 hour, and then the reactor was cooled down to 0 °C. After 10.0 kg of water was slowly added thereto, the reaction mixture was extracted with 6.7 kg of dichloromethane, and the thus-obtained aqueous layer was further extracted with 6.7 kg of dichloromethane. The organic layer was washed with a 15% sodium chloride aqueous solution, treated with 0.5 kg of anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure, to thereby yield 0.98 kg of compound 6a as a yellow oil (Yield: 80.1%). Compound 6a was used in a subsequent process without a separate purification process.
1H NMR (CDCI3, 400MHz) S 3.99 (t, 2H), 3.60 - 3.57 (m, 2H), 2.90 (d, 2H), 2.66 - 2.62 (m, 1H), 2.11 - 2.06 (m, 1H), 1.59 (br, 1H), 1.44 (s, 9H), 0.46 - 0.42 (m, 2H), 0.32 - 0.28 (m, 2H)
Example 2:
Preparation of tert- butyl 3-{[([(9H-fluorene-9- yl)methoxy]carbonyl)(cyclopropyl) ami no] methyl )azetidin-1-carboxylate (Formula 7a: X1=Fmoc)
4.0 kg of dichloromethane was added into a reactor, 300.0 g of tert-butyl 3- [(cyclopropylamino)methyl]azetidin-1-carboxylate prepared in Example 1 and 188.4 g of diisopropylethylamine were sequentially added thereto, and then the reactor was cooled down to 0 °C. 377.2 g of 9-fluorenylmethoxycarbonyl chloride was slowly added into the reactor such that the internal temperature of the reactor did not exceed 20 °C, and the reaction mixture was stirred for 1 hour. 5.0 kg of water was added thereto to wash the organic layer, and the organic layer was further washed with 5.0 kg of a 1 N hydrochloric
acid aqueous solution. The organic layer was further washed with a 15% sodium chloride aqueous solution and treated with 250.0 g of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, to thereby quantitatively yield 576.7 g of compound 7a as a yellow oil. Compound 7a was used in a subsequent process without a separate purification process.
1H NMR (CDCI3, 400MHz) δ 7.72 (d, 2H), 7.56 (d, 2H), 7.36 (t, 2H), 7.30 - 7.26 (m, 2H), 4.52 (d, 2H), 4.17 (t, 1H), 3.89 - 3.85 (m, 2H), 3.56 (m, 2H), 3.30 (m, 2H), 2.60 (m, 1H), 2.28 (m, 1H), 1.43 (s, 9H), 0.61 (m, 2H), 0.45 (m, 2H)
Example 3:
Preparation of tert-butyl 3-[(cyclopropyl-2,2,2-trifluoroacetamido)methyl] azetidin-1 -carboxylate (Formula 7b: X1=Tfa)
2.7 kg of dichloromethane was added into a reactor, and 200.0 g of tert-butyl 3- [(cyclopropylamino)methyl]azetidin-1 -carboxylate prepared in Example 1 was added thereto. 107.3 g of triethylamine was added thereto, and then the reactor was cooled down to 0 °C, 222.7 g of trifluoroacetio acid anhydride was slowly added into the reactor such that the internal temperature of the reactor did not exceed 20 °C, and the reaction mixture was stirred for 1 hour. 2.0 kg of water was added thereto to wash the organic layer, and tine organic layer was further washed with 2.0 kg of a 1 N hydrochloric acid aqueous solution. The organic layer was further washed with a 7% sodium chloride aqueous solution, treated with 100.0 g of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, to thereby quantitatively yield 284.8 g of compound 7b as a white solid and yellow oil. Compound 7b was used in a subsequent process without a separate purification process.
1H NMR (CDCI3, 400MHz) δ 3.99 (t, 2H), 3.60 - 3.57 (m, 2H), 2.90 (d, 2H), 2.68 - 2.60 (m, 1H), 2.10 - 2.06 (m, 1H), 1.44 (s, 9H), 0.46- 0.41 (m, 2H), 0.32 - 0.28 (m, 2H)
Example 4:
Preparation of tert-butyl 3-([cyclopropyl(4- methoxybenzyl)amino]methyl)azetidin-1-carboxylate (Formula 7c: X1=PMB)
14 kg of acetonitrile was added into a reactor, 226.3 g of tert-butyl 3- [(cyclopropylamino)methyl]azetidin-1-carboxylate prepared in Example 1 and 111.3 g of triethylamine were sequentially added thereto, and then the reactor was cooled down to 0 °C. 156.6 g of 4-methoxybenzyl chloride was slowly added thereto and stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure, and 2.0 kg of water and 1.8 kg of ethyl acetate (EA) were added thereto to separate the organic layer. The organic layer was further washed with 2.0 kg of a 0.5N hydrochloric acid aqueous solution.
The organic layer was further washed with a 7% sodium chloride aqueous solution, treated with 100.0 g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure, to thereby obtain 285.8 g of compound 7c as a yellow oil (Yield: 82.5%). Compound 7c was used in a subsequent process without a separate purification process.
1H NMR (CDCI3, 400MHz) δ 7.17 -7.13 (m, 2H), 6.85- 6.82 (m, 2H), 3.88 (t, 2H), 3.80 (s, 3H), 3.65 (s, 2H), 3.47 - 3.43 (m, 2H), 2.78 - 2.72 (m, 1H), 2.66 (d, 2H), 1.72 - 1.67 (m, 1H), 1.41 (s, 9H), 0.51 - 0.47 (m, 2H), 0.37 - 0.34 (m, 2H)
Example 5:
Preparation of (9H-fluorene-9-yl)methyl(azetidin-3- ylmethyl)(cyclopropyl)carbamate hydrochloride (Formula 2a: X1=Fmoc, HA= HCI)
1.0 L of ethanol was added into a reactor, 100.0 g of tert-butyl 3-([([(9H-fluorene- 9-yl)methoxylcarbonyl)(cyclopropyl)amino]methyl)azetidin-1 -carboxylate prepared in Example 2 and 24.8 ml_ of concentrated hydrochloric acid were sequentially added thereto, and then the resultant mixture was heated. The reaction proceeded at reflux temperature for 30 minutes, and then the reaction mixture was concentrated under reduced pressure. 170 ml_ of ethyl acetate and 430 mL of n-hexane were added to the residue, stirred at ambient temperature overnight, filtered, and then dried at 40 °C, to thereby yield 78.2 g of compound 2a (Yield: 91.2%).
1H NMR (CDCI3, 400MHz) δ 9.63 (br, 1 H), 9.40 (br, 1H), 7.75 - 7.70 (m, 2H), 7.60 - 7.55 (m, 2H), 7.38 (t, 2H), 7.32 - 7.29 (m, 2H), 4.52 (d, 2H), 4.18 (t, 1H), 3.99 (m, 2H), 3,81 (m, 2H), 3,44 - 3.28 (m, 2H), 2.94 (m, 1H), 2,27 (m, 1H), 0,60 - 0.59 (m, 2H), 0,43 (m, 2H)
Example 6:
Preparation of N-(azetidi n-3-ylmethyl)-N'-cyclopropyl-2, 2, 2-triflu oro acetamide hydrochloride (Formula 2b: X1=Tfa, HA=HCI)
650 mL of methanol was added into a reactor, 64.5 g of tert-butyl 3-[(cyclopropyl- 2,2,2-trifluoroaoetamido)methyl]azetidin-1-carboxylate prepared in Example 3 and 22.0 mL of concentrated hydrochloric acid were sequentially added thereto, and then the resultant mixture was heated. The reaction proceeded at reflux temperature for 1 hour, and then the reaction mixture was concentrated under reduced pressure. 50 mL of isopropyl alcohol and 600 mL of ethyl acetate were added to the residue, stirred at ambient temperature overnight, filtered, and then dried at 40°C, to thereby yield 44.7 g of compound 2b (Yield: 86.3%).
1H NMR (DMSO-d6, 400MHz) δ 9.39 (br, 2H), 3.98 - 3.93 (m, 2H), 3.77 - 3.72 (m, 2H), 3.67 (d, 2H), 3.09 - 3.01 (m, 1 H), 2.96 - 2.90 (m, 1 H), 0.88 - 0.86 (m, 4H)
Example 7:
Preparation of N-(azetidin-3-ylmethyl)-N'-(4- methoxybenzyl)cyclopropanamine hydrochloride (Formula 2c: X1=PMB, HA= HCI)
520 mL of isopropyl alcohol was added into a reactor, 52.0 g of tert-butyl 3- ([cyclopropyl(4-methoxybenzyl)ami no] methyl)azetidin- 1 -ca rboxy late prepared in Example 4 and 19.0 mL of concentrated hydrochloric acid were sequentially added thereto, and then the resultant mixture was heated. The reaction proceeded at reflux
temperature for 6 hours, and then the reaction mixture was concentrated under reduced pressure. 85 mL of isopropyl alcohol and 210 mL of n-hexane were added to the residue, stirred at ambient temperature overnight, filtered, and then dried under vacuum, to thereby yield 34.0 g of compound 2c (Yield: 80.1%).
1H NMR (CDCI3, 400MHz) δ 9.29 - 9.18 (m, 2H), 7.54 (m, 2H), 6.89 - 6.88 (m, 2H), 4.41 (m, 3H), 4.24 (m, 2H), 3.92 (m, 2H), 3.77 (m, 3H), 3.68 (m, 2H), 2.58 (m, 1H), 1.40 - 1.36 (m, 1H), 1.00 (m, 1H), 0.91 (m, 1H), 0.71 (m, 1H)
Example 8:
Preparation of (9H-fluorene-9-yl)methylcyclopropyl([1 -(2-fluoro-5-[(4-oxo- 3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)carbamate (Formula 4a: X1=Fmoc)
300 mL of dichloromethane was added into a reactor, and 29.8 g of 2-fluoro-5-[(4- oxo-3, 4-dihydrophthalazin-1-yl)methyl] benzoic acid and 17.9 g of 1,1’- carbonyldiimidazole were sequentially added thereto. The reaction proceeded at ambient temperature for 1 hour, and then the reactor was cooled down to 15°C. Then, 42.3 g of
(9H-fluorene-9-yl)methyl(azetidin-3-ylmethyl)(cyclopropyl)carbamate hydrochloride prepared in Example 5 was added thereto, and 19.4 g of di isopropylamine was slowly added thereto. The reaction mixture was stirred at ambient temperature for 1 hour, 300 mL of water was added thereto to wash the organic layer, and then the organic layer was further washed with a 1N hydrochloric acid aqueous solution and a 1N sodium carbonate aqueous solution. The organic layer was further washed with a 5% sodium chloride
aqueous solution, treated with 10.0 g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. 70 mL of ethyl acetate and 350 mL of n-hexane were added to the residue, stirred at ambient temperature overnight, filtered, and then dried at 50 °C, to thereby yield 63.2 g of compound 4a (Yield: 91.3%).
1H NMR (DMSO-d6, 400MHz) δ 12.60 (s, 1H), 8.26 - 8.24 (m, 1H), 7.97 (d, 1H), 7.90 - 7.78 (m, 4H), 7.65 - 7.62 (m, 2H), 7.48 - 7.28 (m, 7H), 4.51 - 4.48 (m, 2H), 4.32 (s, 2H), 4.26 - 4.23 (m, 1H), 3.97 - 3.86 (m, 2H), 3.62 - 3.56 (m, 2H), 3.30 - 3.25 (m, 2H), 2.24 (m, 1H), 1.24 - 1.23 (m, 1H), 0.48 (m, 2H), 0.38 - 0.35 (m, 2H)
Example 9:
Preparation of Ν-cγcΙορrοργΙ-2,2,2-trifluoro--N'-([1-(2-fluoro-5-[(4-oxo-3,4- dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)acetamide (Formula 4b: X1=Tfa)
300 mL of dichloromethane was added into a reactor, and 29.8 g of 2-fluoro-5-[(4- oxo-3, 4-dihydrophthalazin-1-yl)methyl]benzoic acid and then 17.9 g of 1,1’- carbonyldiimidazole were sequentially added thereto. The reaction proceeded at ambient temperature for 1 hour, the reactor was cooled down to 15 °C, and then 28.5 g of N- (azetidin-3-ylmethyl)-N'-cyclopropyl-2,2,2-trifluoro acetamide hydrochloride prepared in Example 6, and then 19.4 g of triethylamine was slowly added thereto. After the reaction mixture was stirred at ambient temperature for 1 hour, 300 mL of water was added to wash the organic layer, and then the organic layer was further washed with a 1N hydrochloric acid aqueous solution and a 1 N sodium carbonate aqueous solution. The
organic layer was washed with a 5% sodium chloride aqueous solution, treated with 10.0 g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. 400 mL of methanol was added to the residue, stirred at 0 °C for 2 hours, filtered, and then dried at 50 °C, to thereby yield 44.7 g of compound 4b (Yield: 89.1%).
1H NMR (DMSO-d6, 400MHz) δ 12.62 (s, 1H), 8.27 - 8.25 (m, 1H), 7.97 (d, 1H), 7.90 -7.86 (m, 1H), 7.83 - 7.79 (m, 1H), 7.48 - 7.46 (m, 2H), 7.24 - 7.19 (m, 1H), 4.33 (s, 2H), 4.14 - 4.02 (m, 2H), 3.79 - 3.62 (m, 4H), 3.01 - 2.91 (m, 1H), 2.88 - 2.85 (m, 1H), 0.87 - 0.68 (m, 4H)
Example 10:
Preparation of 4-(3-[3-([cyclopropyl(4- methoxy benzyl )amino]methy l)azetidin-1 -carbonyl] -4-fluorobenzy I )phthalazin- 1(2H)-one (Formula 4c: X1=PMB)
300 mL of dichloromethane was added into a reactor, and 29.8 g of 2-fluoro-5-[(4- oxo-3, 4-dihydrophthalazin-1-yl)methyl]benzoic acid and 17.9 g of 1,1’- carbonyldiimidazoie were sequentially added thereto. The reaction proceeded at ambient temperature for 1 hour, and then the reactor was cooled down to 15X. Then, 31.1 g of N-(azetidin-3-ylmethyl)-N'-(4-methoxybenzyl)cyclopropanamine hydrochloride prepared in Example 7 was added thereto, and 19.4 g of triethylamine was slowly added thereto. The reaction mixture was stirred at ambient temperature for 1 hour, 300 mL of water was added thereto to wash the organic layer, and then the organic layer was washed with a
1N hydrochloric acid aqueous solution and a 1N sodium carbonate aqueous solution. The organic layer was washed with a 5% sodium chloride aqueous solution, treated with 10.0 g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. 300 mL of toluene was added to the residue, stirred at ambient temperature overnight, filtered, and then dried at 50 °C, to thereby yield 47.0 g of compound 4c (Yield: 81.2%).
1H NMR (DMSO-d6, 400MHz) δ 12.61 (s, 1H), 8.26 (d, 1H), 7.98 (d, 1H), 7.92 - 7.87 (m, 1H), 7.84 - 7.80 (m, 1H), 7.52 - 7.48 (m, 2H), 7.43 - 7.42 (m, 1H), 7.26 - 7.12 (m, 2H), 6.97 (d, 2H), 4.32 (m, 2H), 4.26 (m, 2H), 4.18 - 4.09 (m, 2H), 3.90 - 3.82 (m, 2H), 3.77 (s, 3H), 3.36 (m, 1H), 3.32 (m, 2H), 2.55 - 2.50 (m, 1H), 1.19 - 1.13 (m, 1H), 0.86 - 0.85 (m, 1H), 0.80 - 0.75 (m, 1H), 0.69 - 0.68 (m, 1H)
Example 11:
Preparation of 4-[3-(3-[<cyclopropylamino)methyl]azetidin-1 -carbonyl)-4- fluorobenzyl]phthalazin-1(2H)-one (Formula 1) (1)
150 mL of acetonitrile was added into a reactor, and 30.0 g of (9H-fluorene-9- yl)methyl cyclopropyl([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1- yl)methyl]benzoyl)azetidin-3-yl]methyl)carbamate prepared in Example 8 and 34.5 g of piperidine were sequentially added thereto and stirred at ambient temperature for 1 hour. After the reaction mixture was concentrated under reduced pressure, 300 mL of a 2N hydrochloric acid aqueous solution was added to the residue, stirred for 1 hour, and then filtered through diatomaceous earth. Then, the filtrate was adjusted to pH 9 or greater
with a 1 N sodium hydroxide solution and extracted by adding 300 mL of dichloromethane. The aqueous layer was further extracted by adding 300 mL of dichloromethane thereto, and then the organic layer was mixed therewith, washed with a 5% sodium chloride aqueous solution, and then concentrated. 80 mL of methanol and 40 mL of dichloromethane were added to the residue, and then 150 mL of acetone was slowly added thereto. The resulting solid was stirred at ambient temperature overnight, filtered, and dried at 40 °C to yield 17.5 g of compound 1 (Yield: 90.1%).
1H NMR (DMSO-d6, 400MHz) δ 12.62 (s, 1H), 8.27 - 8.25 (m, 1H), 7.97 (d, 1H), 7.90 - 7.86 (m, 1H), 7.84 - 7.79 (m, 1H), 7.46 - 7.43 (m, 2H), 7.22 - 7.18 (m, 1H), 4.32 (s, 2H), 4.04 - 3.56 (m, 4H), 2.73 - 2.63 (m, 3H), 2.30 (br, 1H), 2.00 - 1.95 (m, 1H), 0.33 - 0.12 (m, 4H)
Example 12:
Preparation of 4-[3-(3-[{cyclopropylamino)methyl]azetidin-1 -carbonyl)-4- fluorobenzyl]phthalazin-1 (2H)-one (Formula 1) (2)
300 mL of methanol was added into a reactor, 30.0 g of N-cyclopropyl-2,2,2- trifluoro-N'-([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3- yl]methyl)acetamide prepared in Example 9, and then the reactor was cooled down to 0 °C . 60 mL of a 20% potassium carbonate aqueous solution was slowly added into the reactor such that the internal temperature of the reactor did not exceed 20 °C, and the reaction mixture was stirred at ambient temperature overnight. 240 mL of water and 300
mL of dichloromethane 300 mL were added thereto to extract the aqueous layer, and then the aqueous layer was further extracted with 300 mL of dichloromethane. Then, the organic layer was mixed therewith, washed with a 5% sodium chloride aqueous solution, and then concentrated. 100 mL of methanol and 50 mL of dichloromethane were added to the residue, and then 200 mL of acetone was slowly added thereto. The resulting solid was stirred at ambient temperature overnight, filtered, and dried at 40 °C, to thereby yield 22.4 g of compound 1 (Yield: 92.1%).
1H NMR {DMSO-d6, 400MHz) δ 12.59 (s, 1 H), 8.27 - 8.25 (m, 1 H), 7.97 (d, 1 H), 7,91 - 7,87 (m, 1H), 7.84 - 7.80 (m, 1H), 7.46 - 7,42 (m, 2H), 7,22 - 7,18 (m, 1H), 4,32 (s, 2H), 4.04 - 3.55 (m, 4H), 2.74 - 2.63 (m, 3H), 2.30 (br, 1H), 2.02 - 1.97 (m, 1H), 0.34 - 0.14 (m, 4H)
Example 13:
Preparation of 4-[3-(3-[{cyclopropylamino)methyl]azetidin-1 -carbonyl )-4- fluorobenzyl]phthalazin-1(2H)-one (Formula 1) (3)
100 mL of trifluoroacetic acid was added into a reactor, and 10.0 g of 4-(3-[3- ([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidin-1-carbonyl]-4- fluorobenzyl)phthalazin-1 (2H)-one prepared in Example 10 was added thereto and stirred at 60 °C for 1 hour. The reactor was then cooled down to 0 °C, 100 mL of dichloromethane 100 mL was added thereto, and then 100 mL of water was slowly added thereto. The aqueous layer was further washed with 100 mL of dichloromethane,
adjusted to pH 9 or greater with a 1 N sodium hydroxide aqueous solution, and then extracted with 100 mL of dichloromethane. The aqueous layer was further extracted with 100 mL of dichloromethane, and the organic layer was mixed therewith, washed with a 5% sodium chloride aqueous solution and then concentrated. 60 mL of methanol and 30 mL of dichloromethane were added to the residue, and 120 mL of acetone was slowly added thereto. The resulting solid was stirred at ambient temperature overnight, filtered, and dried at 40 °C, to thereby yield 13.4 g of compound 1 (Yield: 86.9%).
1H NMR (DMSO-d6, 400MHz) δ 12.59 (s, 1H), 8.27 - 8.25 (m, 1H), 7.98 (d, 1H), 7.91 - 7.87 (m, 1 H), 7.85 - 7.80 (m, 1 H), 7.46 - 7.42 (m, 2H), 7.23 - 7.18 (m, 1 H), 4.32 (s, 2H), 4.04 - 3.55 (m, 4H), 2.74 - 2.63 (m, 3H), 2.30 (br, 1 H), 2.02 - 1.97 (m, 1 H), 0,34 - 0.14 (m, 4H)
Example 14:
Preparation of hydrochloride salt of 4-[3-(3- [(cyclopropy lam ino)methyl]azetidin-1 -carbonyl) -4-fluorobenzyl]phthalazin-1(2H)- one (Formula 1a) (1)
40 mL of methanol and 100 mL of acetone were added into a reactor, 10.0 g of 4- [3-(3-[(cyclopropyiamino)methyl]azetidin-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)- one prepared in Example 11 was added thereto, and then the reactor was cooled down to 0 °C. 2.4 g of concentrated hydrochloric acid was slowly added thereto over 30 minutes,
stirred at ambient temperature overnight, filtered, and dried at 40 °C, to thereby yield 10.4 g of compound 1a (Yield: 95.7% and HPLC purity : 99.86% [area %]).
1H NMR (DMSO-d6, 400MHz) δ 12.61 (s, 1H), 9.37 (br, 2H), 8.27 - 8.25 (m, 1H), 7.98 (d 1 H), 7.93 - 7.88 (m, 1 H), 7.85 - 7.81 (m, 1 H), 7.49 - 7.45 (m, 2H), 7.25 - 7.20 (m,
1H), 4.33 (s, 2H), 4.13 - 3.82 (m, 4H), 3.31 - 3.22 (m, 2H), 3.07 - 3.00 (m, 1H), 2.65 - 2.60 (m, 1H), 0.91 - 0.67 (m, 4H)
Example 15:
Preparation of hydrochloride salt of 4-[3-(3- [(cy clopropy lam in o)methyl]azetid in -1 -carbonyl) -4-fluorobenzyl]phthalazin-1(2H)- one (Formula 1a) (2)
40 mL of ethanol and 60 mL of ethyl acetate were added into a reactor, 10.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidin-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)- one prepared in Example 12 was added thereto, and then the reactor was cooled down to 0 °C. 2.4 g of concentrated hydrochloric acid was slowly added thereto over 30 minutes, stirred at ambient temperature overnight, filtered, and dried at 40 °C, to yield 10.4 g of compound 1a (Yield: 92.1% and HPLC purity : 99.86% [area %]).
1H NMR (DMSO-d6, 400MHz) δ 12,60 (s, 1H), 9.19 (br, 2H), 8.27 - 8.25 (m, 1H), 7.98 (d, 1 H), 7.93 -7.89 (m, 1 H), 7.85 - 7.81 (m, 1 H), 7.50 - 7.44 (m, 2H), 7.25 - 7.20 (m,
1 H), 4.33 (s, 2H), 4.13 - 3.81 (m, 4H), 3.30 - 3.22 (m, 2H), 3.05 - 2.98 (m, 1 H), 2.65 - 2.61 (m, 1H), 0.88 - 0.68 (m, 4H)
Example 16:
Preparation of hydrochloride salt of 4-[3-(3- [(cyclopropy lam ino)methyl]azetid in -1 -carbonyl) -4-fluorobenzyl]phthalazin-1(2H)- one (Formula 1a) (3)
50 mL of ethanol and 100 mL of tert-butylmethylether were added into a reactor,
10.0 9 of 4-[3-(3-[(cyclopropylamino)methyl]azetidin-1-carbonyl)-4- fluorobenzyl]phthalazin-1(2H)-one prepared in Example 13 was added thereto, and then the reactor was cooled down to 0 °C. 2.4 g of concentrated hydrochloric acid was slowly added thereto over 30 minutes, stirred at ambient temperature overnight, filtered, and dried at 40 °C, to yield 10.6 g of compound 1a (Yield: 97.2% and HPLC purity : 99.80% [area %]).
1H NMR (DMSO-d6, 400MHz) δ 12.60 (s, 1H), 9.23 (br, 2H), 8.27 - 8.25 (m, 1H), 7.98 (d, 1 H), 7.93 -7.89 (m, 1 H), 7.85 - 7.81 (m, 1 H), 7.50 - 7.44 (m, 2H), 7.25 - 7.20 (m, 1 H), 4.33 (s, 2H), 4.13 - 3.81 (m, 4H), 3.28 - 3.22 (m, 2H), 3.08 - 2.97 (m, 1 H), 2.66 - 2.62 (m, 1H), 0.89 - 0.68 (m, 4H)
The described embodiments are to be considered in all respects only as illustrative and not restrictive. Those of ordinary skill in the art will recognize that the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The scope of the present invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within the scope of the present invention.
Claims
1. A method of preparing a compound of Formula 1, or a pharmaceutically acceptable salt thereof, [Formula 1]
comprising: deprotecting a compound of Formula 4, [Formula 4]
wherein X1 is an amine protecting group.
2. The method of claim 1 , wherein the compound of Formula 4 is prepared by reacting a compound of Formula 2 [Formula 2]
wherein X1 is an amine protecting group, and HA is an acid which forms an acid addition salt with a compound of Formula 3:
[Formula 3]
3. A method of preparing a compound of Formula 4, comprising reacting a compound of Formula 2 with a compound of Formula 3:
[Formula 2]
[Formula 3]
[Formula 4]
wherein,
X1 is an amine protecting group, and
HA is an acid which forms an acid addition salt.
4. The method of claim 2 or 3, wherein HA is hydrochloric acid (HCI), hydrobromic acid (HBr), or hydro iodic acid (HI).
5. The method of any one of claims 1 to 4, wherein X1 is an amine protecting group selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB).
6. The method of any one of claims 2 to 4, wherein preparing the compound of Formula 4 is carried out in the presence of at least one amide coupling reagent and at least one base.
7. The method of claim 6, wherein the at least one amide coupling reagent is selected from the group consisting of trimethylacetyl chloride, 1 ,T-carbonyldiimidazole, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride(EDC), and any combination thereof, and the at least one base is selected from the group consisting of diisopropylethylamine, triethylamine, N-methyl morpholine, and any combination thereof.
8. The method of any one of claims 1 to 7, comprising reacting the compound of Formula 4 with a non-nucleophilic base, wherein X1 in Formula 4 is fluorenylmethoxycarbonyl (Fmoc).
9. The method of any one of claims 1 to 7, comprising reacting the compound of Formula 4 with an alkali base, wherein X1 in Formula 4 is trifluoroacetyl (Tfa).
10, The method of any one of claims 1 to 7, comprising reacting the compound of Formula 4 with an acid, wherein X1 in Formula 4 is p-methoxybenzyl (PMB).
11. The method of any one of claims 1 to 10, further comprising reacting the compound of Formula 1 with an acid to prepare a pharmaceutically acceptable acid addition salt of the compound of Formula 1.
12. A method of preparing a compound of Formula 2, [Formula 2]
comprising: introducing an amine protecting group X1 into a compound of Formula 6 to prepare a compound of Formula 7; and removing an azetidine nitrogen protecting group X2 from the compound of Formula 7 to prepare the compound of Formula 2:
[Formula 6]
[Formula 7]
wherein, X1 is an amine protecting group,
X2 is an azetidine nitrogen protecting group, and HA is an acid which forms an acid addition salt.
13. A method of preparing a compound of Formula 7, comprising introducing an amine protecting group X1 into a compound of Formula 6
[Formula 6]
[Formula 7]
wherein, X1 is an amine protecting group, and. X2 is an azetidine nitrogen protecting group.
14. The method of claim 12, wherein HA is hydrochloric acid (HCI), hydrobromic acid (HBr), or hydro iodic acid (HI).
15. The method of any one of claims 12 to 14, wherein X1 is an amine protecting group selected from the group consisting of fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), and p-methoxybenzyl (PMB).
16. The method of any one of claims 12 to 15, wherein X2 is an azetidine nitrogen protecting group selected from the group consisting of butoxycarbonyl (Boc), tri phenyl methyl (Trt), and tetrahydropyranyl (THP).
17. A compound of Formula 2: [Formula 2]
wherein, X1 is an amine protecting group, and HA is an acid which forms an acid addition salt.
18. The compound of claim 17, wherein X1 is fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), or p-methoxybenzyl (PMB), and HA is hydrochloric acid (HCI), hydrobromic acid (HBr), or hydroiodic acid (HI).
19. The compound of claim 17 or 18, selected from the group consisting of the following compounds:
(9H-fluorene-9-yl)methyl(azetidin-3-ylmethyl)(cyclopropyl)carbamate hydrochloride of Formula 2a,
[Formula 2a]
N-(azetidin-3-ylmethyl)-N'-cyclopropyl-2,2,2-tnfluoroacetamide hydrochloride of
Formula 2b,
[Formula 2b]
N-(azetidin-3-ylmethyl)-AZ-(4-methoxybenzyl)cyclopropanamine hydrochloride of
Formula 2c,
[Formula 2c]
20. A compound of Formula 4: [Formula 4]
wherein X1 is an amine protecting group.
21. The compound of claim 20, wherein X1 is fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), or p-methoxybenzyl (PMB).
22. The compound of claim 20 or 21 , selected from the group consisting of the following compounds:
(9H-fluorene-9-yl)methyl cyclopropyl ([1-(2-f I uoro-5-[(4-oxo-3, 4- dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)carbamate of Formula 4a, [Formula 4a]
N-cyclopropyl-2,2,2-trifluoro-N'-([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1- yl )methyl]benzoyl)azetidin-3-yl] methyl)acetamid e of Formula 4b,
[Formula 4b]
and
4-(3-[3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetidin-1-carbonyl]-4- fluorobenzyl)phthalazin-1(2H)-one of Formula 4c,
[Formula 4c]
5
23. A compound of Formula 7: [Formula 7]
wherein X1 is an amine protecting group, and X2 is an azetidine nitrogen protecting group.
24. The compound of claim 23, wherein X1 is fluorenylmethoxycarbonyl (Fmoc), trifluoroacetyl (Tfa), or p-methoxybenzyl (PMB), and X2 is an azetidine nitrogen protecting group selected from the group consisting of butoxycarbonyl (Boc), tri phenyl methyl (Trt), and tetrahydropyranyl (THP).
25. The compound of claim 23 or 24, selected from the group consisting of the following compounds: tert-butyl 3-([([(9H-fluorene-9-yl)methoxy]carbonyl)(cyclopropyl) ami no]methyl )azetidin- 1 -carboxylate of Formula 7a,
[Formula 7 a]
terf-butyl 3-[(cyclopropyl-2,2,2-trifluoroacetamido)methyl] azetidin-1 -carboxylate of Formula 7b,
[Formula 7b]
; and tert-butyl 3-([cyclopropyl(4-methoxybenzyl)amino]methyl)azetid in- 1 -carboxylate of Formula 7c,
[Formula 7c]
26. A product comprising a compound of Formula 1 , [Formula 1]
or a pharmaceutically acceptable salt thereof, wherein the compound of Formula 1 , or the pharmaceutically acceptable salt thereof, is produced by a method of any one of claims 1-2, and 4-11.
27, Use of a compound of any of claims 17-25 for the manufacture of a medicament for treating cancer.
28. Use of a compound of any of claims 17-25 for the manufacture of a medicament for treating cancer sensitive to PARP inhibitors.
29. Use of the product of claim 26 for the treatment of a cancer sensitive to PARP inhibitors.
30, A pharmaceutical composition comprising substantially pure drug substance, wherein the drug substance is a compound of Formula 1 [Formula 1]
31. The composition of claim 30, wherein the drug substance is at least 99 percent pure.
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| EP20932070.4A EP4139298A4 (en) | 2020-04-21 | 2020-04-24 | PROCESS FOR PREPARING A PHTHALAZINONE DERIVATIVE AND ITS INTERMEDIATES |
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- 2020-04-24 CN CN202080101999.2A patent/CN115720580B/en active Active
- 2020-04-24 US US16/858,257 patent/US12060345B2/en active Active
- 2020-04-24 KR KR1020227040574A patent/KR20230004724A/en active Pending
- 2020-04-24 EP EP20932070.4A patent/EP4139298A4/en active Pending
- 2020-12-23 TW TW109145639A patent/TWI865700B/en active
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| WO2012019426A1 (en) * | 2010-08-09 | 2012-02-16 | 上海恒瑞医药有限公司 | Phthalazinone derivative, and preparation method and pharmaceutical use thereof |
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| See also references of EP4139298A4 * |
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| CN115720580A (en) | 2023-02-28 |
| US12060345B2 (en) | 2024-08-13 |
| EP4139298A4 (en) | 2024-05-22 |
| CN115720580B (en) | 2025-01-28 |
| JP7626783B2 (en) | 2025-02-07 |
| KR20230004724A (en) | 2023-01-06 |
| US20210323946A1 (en) | 2021-10-21 |
| EP4139298A1 (en) | 2023-03-01 |
| TW202140457A (en) | 2021-11-01 |
| TWI865700B (en) | 2024-12-11 |
| AR121287A1 (en) | 2022-05-04 |
| JP2023536207A (en) | 2023-08-24 |
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